June-July 2020

CORNEA

Research Highlight
Breakthrough in Fuchs research


by Liz Hillman Editorial Co-Director


Retroillumination image showing that Fuchs dystrophy affects central cornea, sparing the periphery or areas covered by the eyelids
Source: Ula Jurkunas, MD

A new study is being hailed as a breakthrough in Fuchs endothelial dystrophy research, providing explanations to several questions surrounding this potentially blinding disorder.1

Why is the disease found in the central cornea primarily?

As a clinician scientist, Ula Jurkunas, MD, said she has had the longstanding observation that Fuchs dystrophy develops in the center of the cornea and spreads to the periphery.
“A lot of times, if you lift the eyelid of the patient, the upper cornea that is covered by the eyelid has no findings, but it is the area that is interpalpebral, meaning it is exposed to sunlight, [where you see guttae],” Dr. Jurkunas said.
With these observations and findings from earlier studies showing the involvement of oxidative stress in Fuchs pathogenesis, Dr. Jurkunas and coinvestigators hypothesized that ultraviolet light was a physiological stressor involved in the mechanism of Fuchs.
They developed a mouse model to test this hypothesis, shining varying doses of ultraviolet light into mouse eyes (non-irradiated eyes served as controls) and following up for several months. Researchers identified alterations in mouse corneal endothelial cell morphology, cell density, and “guttae-like lesions” in irradiated eyes, which Dr. Jurkunas said were similar to those seen in human Fuchs patients.

Why is it more common in women than men?

Fuchs is known to have a genetic component, but women also seem to get it more than men, Dr. Jurkunas said. When studying their mouse model, Dr. Jurkunas said they unexpectedly saw significantly more female mice with endothelial cell changes after UV light exposure.
“They developed Fuchs earlier and in a more severe form,” Dr. Jurkunas said.
The researchers studied the effect of UV-A light on human corneal cells in vitro and identified a pathway that showed increased expression of the enzyme CYP1B1. This enzyme is involved in an estrogen metabolite pathway that leads to DNA damage.
“I think men and women have this enzyme, but it is probably the tissues are more estrogen rich in females and that enzyme is expressed at higher levels in female tissues. However, it is present in men, and probably the people who do develop this, even men, have activation of this enzyme,” Dr. Jurkunas said.

Is there a therapeutic pharmaceutical target?

From there the researchers wondered about reversing the effects of this oxidative stress. N-acetylcysteine is well known in the scientific literature as a vast antioxidant, Dr. Jurkunas said. In ophthalmology, it’s used for filamentary keratitis and severe dry eye. What’s more, Dr. Jurkunas said in their previous in vitro and cell studies, N-acetylcysteine was able to reverse the mechanism involved in Fuchs, so they tested it in the animal model, giving it to some mice in drinking water for 3 months after UV light exposure.
“The mice that were drinking N-acetylcysteine had significant reduction of the findings, both female and male mice,” Dr. Jurkunas said.
While this points to a potential therapeutic target, a research pathway for Fuchs, Dr. Jurkunas said clinical studies are needed to prove it, and it’s too early for ophthalmologists to start recommending it to patients.
In the meantime, Dr. Jurkunas said doctors can advise that patients protect their eyes from the sun by wearing hats and/or sunglasses.
“For a long time [Fuchs] was viewed as a genetic-only disorder. A lot of research focused on finding a gene there. I think this is the first study showing that there are modifiable risk factors, like UV light,” Dr. Jurkunas said.

About the doctor

Ula Jurkunas, MD
Associate professor of ophthalmology
Massachusetts Eye and Ear Infirmary
Harvard Medical School
Boston, Massachusetts

Reference

1. Liu C, et al. Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected. Proc Natl Acad Sci USA. 2020;117:573–583.

Relevant disclosures

Jurkunas: Patent filed for N-acetylcysteine compound

Contact

Jurkunas: Ula_Jurkunas@meei.harvard.edu

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